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Electroconvulsive therapy (ECT) is one of the most efficacious interventions for treatment-resistant depression. Despite its efficacy, ECTs neural mechanism of action remains unknown. Although ECT has been associated with slowing in the electroencephalogram (EEG), how this change relates to clinical improvement is unresolved. Until now, increases in slow-frequency power have been assumed to indicate increases in slow oscillations, without considering the contribution of aperiodic activity, a process with a different physiological mechanism. In this exploratory study of nine MDD patients, we show that aperiodic activity, indexed by the aperiodic exponent, increases with ECT treatment. This increase better explains EEG slowing when compared to power in oscillatory peaks in the delta (1-3 Hz) range and is correlated to clinical improvement. In accordance with computational models of excitation-inhibition balance, these increases in aperiodic exponent are linked to increasing levels of inhibitory activity, suggesting that ECT might ameliorate depressive symptoms by restoring healthy levels of inhibition in frontal cortices.

Methylation of cytosines is a prototypic epigenetic modification of the DNA. It has been implicated in various regulatory mechanisms across the animal kingdom and particularly in vertebrates. We mapped DNA methylation in 580 animal species (535 vertebrates, 45 invertebrates), resulting in 2443 genome-scale DNA methylation profiles of multiple organs. Bioinformatic analysis of this large dataset quantified the association of DNA methylation with the underlying genomic DNA sequence throughout vertebrate evolution. We observed a broadly conserved link with two major transitions-once in the first vertebrates and again with the emergence of reptiles. Cross-species comparisons focusing on individual organs supported a deeply conserved association of DNA methylation with tissue type, and cross-mapping analysis of DNA methylation at gene promoters revealed evolutionary changes for orthologous genes. In summary, this study establishes a large resource of vertebrate and invertebrate DNA methylomes, it showcases the power of reference-free epigenome analysis in species for which no reference genomes are available, and it contributes an epigenetic perspective to the study of vertebrate evolution.

Background(S)-ketamine is a glutamatergic drug with potent and rapid acting effects for the treatment of depression. Little is known about the effectiveness of intranasal (S)-ketamine for treating patients with comorbid depression and post-traumatic stress disorder (PTSD).MethodsWe performed a retrospective case series analysis of clinical outcomes in 35 Veterans with co-morbid depression and PTSD who were treated with intranasal (S)-ketamine treatments at the VA San Diego Neuromodulation Clinic between Jan 2020 and March 2021. Veterans were not randomized or blinded to treatment. The primary outcome measured was a change in patient health questionnaire-9 (PHQ-9) and PTSD Checklist for DSM-5 (PCL-5) scores across the first 8 treatments (induction period) using a repeated measures analysis of variance (ANOVA). In a smaller sub-group (n = 19) of Veterans who received at least 8 additional treatments, we analyzed whether intranasal (S)-ketamine continued to show treatment effects. Finally, we performed a sub-group and correlation analyses to understand how changes in PHQ-9 and PCL-5 scores were related across treatments.FindingsDuring the induction phase of treatment there was an absolute reduction of 5.1 (SEM 0.7) on the patient health questionnaire-9 (PHQ-9) rating scale for depression, from 19.8 (SEM 0.7) at treatment 1 to 14.7 (SEM 0.8) at treatment 8 (week 4) (F(7238) = 8.3, p = 1e-6, partial η2 = 0.2). Five Veterans (14%) showed a clinically meaningful response (50% reduction in PHQ-9 score) at treatment 8. There was an absolute reduction of 15.5 +/- 2.4 on the patient checklist 5 (PCL-5) rating scale for PTSD, from 54.8 (SEM 2) at treatment 1 down to 39.3 (SEM 2.5) at treatment 8 (F(7238) = 15.5, p = 2e-7, partial η2 = 0.31). Sixteen Veterans (46%) showed a clinically meaningful response (reduction in PCL-5 of > 30%) in PTSD. Change in PHQ-9 correlated with change in PCL-5 at treatment 8 (r = 0.47, p = 0.005), but a decrease in PTSD symptoms were observable in some individuals with minimal anti-depressant response.InterpretationsWhile this is an open-label retrospective analysis, our results indicate that both depression and PTSD symptoms in Veterans with dual-diagnoses may improve with repeated intranasal (S)-ketamine treatment. The effects of (S)-ketamine on PTSD symptoms were temporally and individually distinct from those on depression, suggesting potentially different modes of action on the two disorders. This work may warrant formal randomized controlled studies on the effects of intranasal (S)-ketamine for individuals with co-morbid MDD and PTSD.FundingVA Center of Excellence in Stress and Mental Health, VA ORD (Career Development Award to DSR), Burroughs-Wellcome Fund Award (DSR), NIMH (EL).

BackgroundRacemic (R,S)-ketamine is a glutamatergic drug with potent and rapid acting antidepressant effects. An intranasal formulation of (S)-ketamine was recently approved by the US Food and Drug Administration (FDA) to be used in individuals with treatment-resistant depression (TRD). There are no data directly comparing outcomes on depression or other comorbidities between these two formulations of ketamine. However, recent meta-analyses have suggested that IV racemic ketamine may be more potent than IN-(S)-ketamine.MethodsWe retrospectively analyzed clinical outcomes in 15 Veterans with comorbid TRD and post-traumatic stress disorder (PTSD) who underwent ketamine treatment at the VA San Diego Neuromodulation Clinic. All Veterans included in this analysis were given at least 6 intranasal (IN)-(S)-ketamine treatments prior to switching to treatment with IV racemic ketamine.ResultsVeterans receiving ketamine treatment ( across both IN-(S)-ketamine and IV-(R,S)-ketamine) showed significant reductions in both the Patient Health Questionnaire-9 (PHQ-9), a self-report scale measuring depression symptoms (rm ANOVA F(14,42) = 12.6, p

Single ventricle physiology and palliation via the Fontan operation lead to a series of cardiovascular changes. In addition, organs such as the kidneys and liver have been shown to experience insults and subsequent injury. This has led to routine surveillance of patients. We present findings from a small cohort of patients that was deeply phenotyped to illustrate the need for comprehensive evaluation. A cohort of four Fontan patients with fairly high cardiovascular function was recruited 5-10 years post-Fontan. Patients underwent a rigorous clinical work-up after which a research MRI scan was performed during which (I) data were obtained during exercise to evaluate changes in stroke volume during supine exercise and (II) magnetic resonance angiograms with phase-contrast images were obtained for computational modeling of flows through the Fontan circulation at rest. Clinical measures were consistent with a fairly homogeneous high function cohort (peak oxygen consumption >20 mL/kg/min, robust response to exercise, peak ventilatory efficiency below levels associated with heart failure, MR-derived ejection fraction >50%). Liver evaluation did not reveal clear signs of cirrhosis or extensive fibrosis. However, we observed considerable variability (27-162%) in the increase in stroke index with exercise [100%±64% increase, 53.9±17.4 mL/beat m2 (rest), 101.1±20.7 mL/beat m2, (exercise)]. Computational flow modeling at rest in two patients also showed marked differences in flow distribution and shear stress. We report marked differences in both changes in stroke index during an exercise MRI protocol as well as computational flow patterns at rest suggesting different compensation strategies may be associated with high functioning Fontan patients. The observed heterogeneity illustrates the need for deep phenotyping to capture patient-specific adaptive mechanisms.

ObjectivesTo determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of a 6-week course of atorvastatin in patients with acute Kawasaki disease with coronary artery (CA) aneurysm (CAA).Study designThis was a Phase I/IIa 2-center dose-escalation study of atorvastatin (0.125-0.75 mg/kg/day) in 34 patients with Kawasaki disease (aged 2-17 years) with echocardiographic evidence of CAA. We measured levels of the brain metabolite 24(S)-hydroxycholesterol (24-OHC), serum lipids, acute-phase reactants, liver enzymes, and creatine phosphokinase; peripheral blood mononuclear cell populations; and CA internal diameter normalized for body surface area before atorvastatin treatment and at 2 and 6 weeks after initiation of atorvastatin treatment.ResultsA 6-week course of up to 0.75 mg/kg/day of atorvastatin was well tolerated by the 34 subjects (median age, 5.3 years; IQR, 2.6-6.4 years), with no serious adverse events attributable to the study drug. The areas under the curve for atorvastatin and its metabolite were larger in the study subjects compared with those reported in adults, suggesting a slower rate of metabolism in children. The 24-OHC levels were similar between the atorvastatin-treated subjects and matched controls.ConclusionsAtorvastatin was safe and well tolerated in our cohort of children with acute Kawasaki disease and CAA. A Phase III efficacy trial is warranted in this patient population, which may benefit from the known anti-inflammatory and immunomodulatory effects of this drug.

Jacobsen syndrome (OMIM #147791) is a rare contiguous gene disorder caused by deletions in distal 11q. The clinical phenotype is variable and can include dysmorphic features, varying degrees of intellectual disability, behavioral problems including autism and attention deficit hyperactivity disorder, congenital heart defects, structural kidney defects, genitourinary problems, immunodeficiency, and a bleeding disorder due to impaired platelet production and function. Previous studies combining both human and animal systems have implicated several disease-causing genes in distal 11q that contribute to the Jacobsen syndrome phenotype. One gene, ETS1, has been implicated in causing congenital heart defects, structural kidney defects, and immunodeficiency. We performed a comprehensive phenotypic analysis on a patient with congenital heart disease previously found to have a de novo frameshift mutation in ETS1, resulting in the loss of the DNA-binding domain of the protein. Our results suggest that loss of Ets1 causes a "partial Jacobsen syndrome phenotype" including congenital heart disease, facial dysmorphism, intellectual disability, and attention deficit hyperactivity disorder.

BackgroundWe sought to determine if fever in the early postintravenous immunoglobulin (IVIG) time period (first 36 hours after IVIG completion) for Kawasaki disease, with or without additional infliximab, can predict IVIG resistance and coronary artery abnormalities (CAA).MethodsAcute Kawasaki disease subjects enrolled in a clinical trial of infliximab plus IVIG (n = 96) versus placebo/IVIG (n = 94) had temperatures recorded every 6 hours after completion of IVIG infusion. Fever was defined as temperature >38.0°C; patients with persistent or recrudescent fever >36 hours after completion of IVIG were classified as IVIG resistant. Multivariable logistic regression by fever pattern was performed to predict outcomes (IVIG resistance and CAA).ResultsThere was no difference in the time to defervescence between the infliximab/IVIG group (n = 96) versus placebo/IVIG group (n = 94). There was no fever after completion of IVIG in the majority of subjects [66% of those with no CAA (n = 139) and 76.5% of those with CAA, (n = 51)]. Although subjects with at least 1 fever 24-36 hours post-IVIG had a higher probability of IVIG resistance [odds ratio = 30.6 (95% confidence interval: 6.7-139.8); P < 0.0001], fever at 24-36 hours was not associated with higher likelihood of CAA. There were also 11% (n = 19) of IVIG responders who had fever at 24-36 hours post-IVIG. The majority of subjects with CAA (43 of 51, 84.3%) were identified by the initial echocardiogram, so the effect of fever on development of CAA could not be assessed.ConclusionsFever in the first 36 hours after IVIG completion is not predictive of CAA. Our data support refraining from retreatment until 36 hours after completion of IVIG.

Hollow/porous nanoparticles, including nanocarriers, nanoshells, and mesoporous materials have applications in catalysis, photonics, biosensing, and delivery of theranostic agents. Using a hierarchical template synthesis scheme, we have synthesized a nanocarrier mimicking a golf ball, consisting of (i) solid silica core with a pitted gold surface and (ii) a hollow/porous gold shell without silica. The template consisted of 100 nm polystyrene beads attached to a larger silica core. Selective gold plating of the core followed by removal of the polystyrene beads produced a golf ball-like nanostructure with 100 nm pits. Dissolution of the silica core produced a hollow/porous golf ball-like nanostructure.

BackgroundKawasaki disease, the most common cause of acquired heart disease in developed countries, is a self-limited vasculitis that is treated with high doses of intravenous immunoglobulin. Resistance to intravenous immunoglobulin in Kawasaki disease increases the risk of coronary artery aneurysms. We assessed whether the addition of infliximab to standard therapy (intravenous immunoglobulin and aspirin) in acute Kawasaki disease reduces the rate of treatment resistance.MethodsWe undertook a phase 3, randomised, double-blind, placebo-controlled trial in two children's hospitals in the USA to assess the addition of infliximab (5 mg per kg) to standard therapy. Eligible participants were children aged 4 weeks-17 years who had a fever (temperature ≥38·0°C) for 3-10 days and met American Heart Association criteria for Kawasaki disease. Participants were randomly allocated in 1:1 ratio to two treatment groups: infliximab 5 mg/kg at 1 mg/mL intravenously over 2 h or placebo (normal saline 5 mL/kg, administered intravenously). Randomisation was based on a randomly permuted block design (block sizes 2 and 4), stratified by age, sex, and centre. Patients, treating physicians and staff, study team members, and echocardiographers were all masked to treament assignment. The primary outcome was the difference between the groups in treatment resistance defined as a temperature of 38·0°C or higher at 36 h to 7 days after completion of the infusion of intravenous immunoglobulin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00760435.Findings196 patients were enrolled and randomised: 98 to the infliximab group and 98 to placebo. One patient in the placebo group was withdrawn from the study because of hypotension before receiving treatment. Treatment resistance rate did not differ significantly (11 [11·2%] for infliximab and 11 [11·3%] for placebo; p=0·81). Compared with the placebo group, participants given infliximab had fewer days of fever (median 1 day for infliximab vs 2 days for placebo; p

The most common health-related apps are lifestyle apps, i.e., fitness, nutrition, diet, and meditation apps, which account for half of all m-health apps on the market. Mobile app-based interventions have been shown to be effective in improving diet-related health outcomes. The aim of this study is to map the usage patterns of lifestyle apps (fitness, diet, and relaxation apps) and identify the role of each factor in the usability of MAUQ (m-Health App Usability Questionnaire) factor - ease of use, interface satisfaction, and usefulness - in overall satisfaction. Data were collected through an online survey in Hungary with 348 users of various lifestyle applications, i.e., fitness (30.2%), nutrition (31.3%), and mindfulness (38.5%) apps. Respondents showed a preference for free apps over paid ones and predominantly used iOS operating systems. The partial least squares structural equation modelling (PLS-SEM) method was used to identify the role of usability dimensions in overall satisfaction. The satisfaction of lifestyle app users is positively influenced by 'Ease of Use' and 'Interface and Satisfaction'. However, effectiveness (positive physical and mental health outcomes) negatively influences satisfaction. Research can be particularly useful for app developers, as usability and design (features) play a particularly important role in satisfaction, so these are primary considerations in development. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to add further knowledge about the usefulness of the Voice Range Profile (VRP) assessment in clinical settings and research by analyzing VRP dual-microphone equipment precision, reliability, and room effect. Method: Test-retest studies were conducted in an anechoic chamber and an office: (a) comparing sound pressure levels (SPLs) from a dual-microphone VRP device, the Voice Profiler, when given the same input repeatedly (test-retest reliability); (b) comparing SPLs from 3 devices when given the same input repeatedly (intervariation); and (c) assessing the room effect. Results: (a) The mean standard deviation across 17 measurement points was 0.7 dB for 1 device. (b) One device was less precise than the other 2 devices. All devices presented high SPLs at low frequencies compared with the reference. (c) Mean SPLs were almost equal in the anechoic chamber and the office. Conclusions: The high test-retest reliability of the dual-microphone VRP equipment, especially in general office surroundings, is a positive finding. Attention must be paid to specific factors such as using the same device when comparing the same voice before and after treatment, caution in headset placement, and manual recalibrations when automatic recalibration occurs. We suggest recalibrations verified with a reference source at regular intervals.

Toxoplasma gondii is an intracellular parasite that infects a wide range of warm-blooded species. Rats vary in their susceptibility to this parasite. The Toxo1 locus conferring Toxoplasma resistance in rats was previously mapped to a region of chromosome 10 containing Nlrp1. This gene encodes an inflammasome sensor controlling macrophage sensitivity to anthrax lethal toxin (LT) induced rapid cell death (pyroptosis). We show here that rat strain differences in Toxoplasma infected macrophage sensitivity to pyroptosis, IL-1β/IL-18 processing, and inhibition of parasite proliferation are perfectly correlated with NLRP1 sequence, while inversely correlated with sensitivity to anthrax LT-induced cell death. Using recombinant inbred rats, SNP analyses and whole transcriptome gene expression studies, we narrowed the candidate genes for control of Toxoplasma-mediated rat macrophage pyroptosis to four genes, one of which was Nlrp1. Knockdown of Nlrp1 in pyroptosis-sensitive macrophages resulted in higher parasite replication and protection from cell death. Reciprocally, overexpression of the NLRP1 variant from Toxoplasma-sensitive macrophages in pyroptosis-resistant cells led to sensitization of these resistant macrophages. Our findings reveal Toxoplasma as a novel activator of the NLRP1 inflammasome in rat macrophages.

ObjectiveThe current study explored the clinical meaningfulness of distinguishing subjective (SBE) from objective binge eating (OBE) among individuals with threshold/subthreshold bulimia nervosa (BN). We examined relations between OBEs and SBEs and eating disorder symptoms, negative affect, and personality dimensions using both a group comparison and a continuous approach.MethodParticipants were 204 adult females meeting criteria for threshold/subthreshold BN who completed questionnaires related to disordered eating, affect, and personality.ResultsGroup comparisons indicated that SBE and OBE groups did not significantly differ on eating disorder pathology or negative affect, but did differ on two personality dimensions (cognitive distortion and attentional impulsivity). Using the continuous approach, we found that frequencies of SBEs (not OBEs) accounted for unique variance in weight/shape concern, diuretic use frequency, depressive symptoms, anxiety, social avoidance, insecure attachment, and cognitive distortion.DiscussionSBEs in the context of BN may indicate broader areas of psychopathology.

Anthrax lethal toxin (LT) is a bipartite protease-containing toxin and a key virulence determinant of Bacillus anthracis. In mice, LT causes the rapid lysis of macrophages isolated from certain inbred strains, but the correlation between murine macrophage sensitivity and mouse strain susceptibility to toxin challenge is poor. In rats, LT induces a rapid death in as little as 37 minutes through unknown mechanisms. We used a recombinant inbred (RI) rat panel of 19 strains generated from LTsensitive and LT-resistant progenitors to map LT sensitivity in rats to a locus on chromosome 10 that includes the inflammasome NOD-like receptor (NLR) sensor, Nlrp1. This gene is the closest rat homolog of mouse Nlrp1b, which was previously shown to control murine macrophage sensitivity to LT. An absolute correlation between in vitro macrophage sensitivity to LT-induced lysis and animal susceptibility to the toxin was found for the 19 RI strains and 12 additional rat strains. Sequencing Nlrp1 from these strains identified five polymorphic alleles. Polymorphisms within the N-terminal 100 amino acids of the Nlrp1 protein were perfectly correlated with LT sensitivity. These data suggest that toxin-mediated lethality in rats as well as macrophage sensitivity in this animal model are controlled by a single locus on chromosome 10 that is likely to be the inflammasome NLR sensor, Nlrp1.

BackgroundWe have used a genetical genomic approach, in conjunction with phenotypic analysis of alcohol consumption, to identify candidate genes that predispose to varying levels of alcohol intake by HXB/BXH recombinant inbred rat strains. In addition, in two populations of humans, we assessed genetic polymorphisms associated with alcohol consumption using a custom genotyping array for 1,350 single nucleotide polymorphisms (SNPs). Our goal was to ascertain whether our approach, which relies on statistical and informatics techniques, and non-human animal models of alcohol drinking behavior, could inform interpretation of genetic association studies with human populations.ResultsIn the HXB/BXH recombinant inbred (RI) rats, correlation analysis of brain gene expression levels with alcohol consumption in a two-bottle choice paradigm, and filtering based on behavioral and gene expression quantitative trait locus (QTL) analyses, generated a list of candidate genes. A literature-based, functional analysis of the interactions of the products of these candidate genes defined pathways linked to presynaptic GABA release, activation of dopamine neurons, and postsynaptic GABA receptor trafficking, in brain regions including the hypothalamus, ventral tegmentum and amygdala. The analysis also implicated energy metabolism and caloric intake control as potential influences on alcohol consumption by the recombinant inbred rats. In the human populations, polymorphisms in genes associated with GABA synthesis and GABA receptors, as well as genes related to dopaminergic transmission, were associated with alcohol consumption.ConclusionOur results emphasize the importance of the signaling pathways identified using the non-human animal models, rather than single gene products, in identifying factors responsible for complex traits such as alcohol consumption. The results suggest cross-species similarities in pathways that influence predisposition to consume alcohol by rats and humans. The importance of a well-defined phenotype is also illustrated. Our results also suggest that different genetic factors predispose alcohol dependence versus the phenotype of alcohol consumption.

Normative data are important in the clinical setting of Speech and Language Pathology. The purpose of this study was to develop a normative reference dataset of voice range profiles from young females. Descriptive study including a prospective collection of voice range profile data. Voice range profile recordings from 39 females with healthy voices aged 18 to 28 years were conducted. Seven voice range profile variables were analyzed: minimum and maximum fundamental frequency and intensity, semitone and intensity ranges, and voice range profile area. Descriptive statistical methods were applied. An age-specific voice range profile normative dataset was established. The mean values and standard deviations were as follows: semitone range 34.7 ± 3.9 ST, minimum fundamental frequency 143.6 ± 21.7 hertz, maximum fundamental frequency 1063.5 ± 160 hertz, intensity range 65.6 ± 5.0 dB, minimum intensity 43.2 ± 2.5 dB SPL, maximum SPL 108.9 ± 5.1 dB SPL, and voice range profile area 1346 ± 222 cells. A normative dataset usable for optimization of future voice assessments has been established. It may especially benefit evaluation and treatment planning for younger females suffering from vocal fold nodules. [ABSTRACT FROM AUTHOR]

Acceptance and Commitment Therapy (ACT) is an empirically supported treatment for a variety of clinical concerns and has over 1000 randomized controlled trials (RCTs). ACT may be a potentially effective treatment for racial, sexual orientation and gender diverse people who experience unique stressors related to their identities and higher rates of psychopathology and have unique mental health considerations. Despite this, there remains a lack of inclusion of reporting and inclusion of these communities in psychological research. This lack of inclusion of minority populations limits the generalizability of the findings of RCTs to those populations. Further, although there is a growing number of minority graduate students and trainees, this increased diversity often does not extend to their principal investigators. The current study reviews racial, sexual, and gender minority inclusion of participants as well as of principal investigators in 75 ACT RCTs performed in the United States (n = 10,914). Of these, 73% were White, 11% were Black, 5% were Latine, 3% were Asian, 2% were Native American, 0.4% were Pacific Islander, 0.1% were Middle Eastern, and 3% were multiracial while 1% were reported as Other and another 1% as Unknown. Of the 75 studies reviewed, 5 reported on sexual orientation and 73% of participants were heterosexual, 7% were gay or lesbian, 5% were bisexual, 2% were pansexual, 4% were asexual, 1% were queer, 1% were questioning, and 1% were reported as Other and 7% as Unknown (n = 297). Only two studies reported on gender identity beyond men and women, with one study including all cisgender participants and one study reporting that 2% of participants were nonbinary. Of the 32 PIs that responded, 94% were White, 2% were Mixed, and 2% were Asian. In terms of sexual orientation and gender identity, one PI was gay, one was asexual, and cisgender women authored 26% of studies. These results indicated that despite Black participants being more accurately represented, Latine and Asian participants were largely underrepresented. Regardless of level of representation, the numbers of racial, sexual, and gender minority participants were still limited and therefore conclusions cannot be made about the generalizability of ACT for these populations. Recommendations for more inclusive practices are provided. We discuss limitations to this review and the implications of PI refusal to report their sexual and gender identity. • ACT is a potentially beneficial treatment modality for ethnoracial, sexual, and gender minorities. • Underrepresentation of minority groups in ACT literature limits the generalizability of existing findings. • There was a near absence of reporting on sexual orientation and gender among the sample. • There is an underrepresentation of minority groups among PIs despite ACT researchers' value of mentoring trainees of color. [ABSTRACT FROM AUTHOR]

These two commentaries on the article "Head Start: Challenges and Training Needs" (Leah Buscemi and others) discuss the role of technical assistance providers in helping grantees work with community institutions, especially local education agencies; the need for formal written interagency agreements; the necessity for creating parent training and support systems; and the need for building interagency collaboration. (CR)